Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses 1.1. Cyclopropanation Strategies in Recent Total Syntheses1 1.2. 1. Cyclopropanation Methods 1.1 Simmons–Smith Cyclopropanation In 1958, H. E. Simmons and R. D. Smith at DuPont reported the formal cycloaddition of methylene and various olefins by treatment of diiodomethane with zinc-copper couple Zn(Cu).2 The synthetic utility of this method derives mainly from the large scope of olefins that can be employed as substrates as well as stereospecificity of the transformation,3 so that the stereochemical information of the olefin is transferred to the product. A strong directing-effect may be observed, when the substrate bears Lewis basic heteroatoms in proximity to the olefin.4 A representative, simple example is shown in Scheme 1, in which cyclohexene-1-ol (1) is exposed to CH2I2 and Zn(Cu) providing 2 as a single diastereomer in 63% yield. Scheme 1: Simmons–Smith cyclopropanation of cyclohexene-1-ol (1). In 1959, Wittig and Schwarzenbach reported that exposure of diazomethane to zinc iodide in ether 5 provided IZnCH2I. Furthermore, Furukawa et al. developed a method that has been widely adopted for 6 the generation of the zinc carbenoid in which diiodomethane is treated with ZnEt2. The carbenoid species generated under the Furukawa conditions displays high reactivity with electron-rich olefins such as styrenes, enol ethers and enamines as well as for substrates containing Lewis basic directing groups. In 1991, Denmark and Edwards showcased the superior cyclopropanation properties of a carbenoid 7 generated from ZnEt2 and ClCH2I. Shi and co-workers have noted that the zinc carbenoid can be rendered more reactive by ligand exchange process.8 In their landmark study, one equivalent of Brønsted acids, such as alcohols, amines, carboxylic or sulfonic acids, was added to equimolar amounts of ZnEt2 followed by one equivalent of CH2I2. The electron-withdrawing effect of trifluoroacetic acetate as a ligand on zinc is suggested to trigger a dramatic increase in the reaction rate. To date, the generated (F3CCO2)ZnCH2I carbenoid represents one of the most reactive reagents for cyclopropanation. Moreover, Charette and co-workers reported phosphoric acid-derived zinc carbenoids also display enhanced reactivity.9 1.2 Diazo-Derived Carbenoids The discovery that metal salts catalyze the decomposition of diazo compounds dates back to 1906, when Silberrad and Roy investigated the effect of copper dust on ethyl diazoacetate.10 A milestone was reached in the 1960’s, when catalytic homogeneous diazo decomposition was enabled by soluble copper 11 complexes. A decade later, Teyssie discovered that Pd(OAc)2 and Rh2(OAc)4 are suitable alternatives to copper salts.12 A Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses Scheme 2. Diazo-derived carbenoids for the cyclopropanation of olefins. Several important aspects need to be taken into account when consideration is given to the use of a diazo-derived carbenoid for a cyclopropanation reaction in the synthesis of complex molecules (Scheme 2). Firstly, because alkyldiazo compounds lacking stabilizing groups are considered capricious, they are typically generated in situ.13 Secondly, in case of intermolecular cyclopropanation (3 → 4) slow addition of the diazo compound to a mixture of the olefin and a metal catalyst may be necessary in order to avoid carbene dimerization.14 Thirdly, chemoselective discrimination between cyclopropanation and C–H insertion pathways can be an important issue. In this respect, elegant studes by Padwa and Doyle showcase that chemoselectivity can be significantly influenced by the nature of the catalyst employed.15 Even for diazoketone 7, possessing both, a γ,δ-olefin and a γ-methine C–H, complete selectivity can be achieved. As shown in Scheme 3, while Rh2(OAc)4 produces a 1:1 mixture of 8 and 9, Rh2(pfb)4 furnishes solely the product of C–H insertion. In contrast, the use of Rh2(cap)4 produced only cyclopropane 8. Scheme 3. Chemoselectivity study between C–H insertion and cyclopropanation by Padwa and Doyle. The intramolecular variant of this transformation (cf. Scheme 2, 6 → 5) has gained considerable popularity in natural product synthesis, as two rings can be stereoselectively generated in a single step and, depending on the olefin employed, highly substituted cyclopropanes can be accessed.16 1.3 Free Carbenes As early as 1862, Geuther discovered that chloroform undergoes decomposition in alkaline alcohol solutions.17 Almost 100 years later, Doering and Hoffmann treated a mixture of cyclohexene and a B Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses solution of KOt-Bu in t-BuOH with chloroform and observed a vigorously exothermic reaction (Scheme 4).18 The product formed was identified as 7,7-dichlorobicyclo[4.1.0]heptane (17) and its formation was attributed to the generation of dichlorocarbene (15) via base-mediated α-elimination. Several years later, Cory and McLaren showcased the enormous potential of this method during their total synthesis of ishwarane (21).19 Olefin 18 was treated with tetrabromomethane and an excess of methyl lithium at −78 °C, mediating the formation of dibromocyclopropane 19. Upon warming of the reaction mixture to –30 °C, lithium-halogen exchange and subsequent α-elimination occurred, generating cyclopropylcarbene 20, which participated in a C–H insertion reaction to yield ishwarane (21). Scheme 4. Formation of dichlorocarbene and total synthesis of ishwarane by Cory and McLaren. In 1967, Crandall and Lin discovered that α-lithiated epoxides are prone to undergo elimination, leading to carbene formation.20 When epoxide 22 was exposed to t-BuLi, cyclopropanol 23 was isolated as a minor product in 9% yield (Scheme 5). Intriguingly, the anti-isomer was the only observed product, a finding attributed cycloaddition proceeding through chair-like transition state 24.21 Scheme 5. α-Lithiation and elimination of epoxides. C Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses During their investigation of the α-deprotonation of epoxides, Mioskowski and co-workers discovered that epoxide 25 furnished cyclopropane 26 via carbene 27, albeit in low yield.22 In the early 2000’s, Hodgson became interested in optimizing this intriguing transformation in light of the fact that enantioenriched epoxides are widely available via Jacobsen hydrolytic kinetic resolution.23,24 After a laborious screening, Hodgson and co-workers found that high yields (60-84%) can be obtained by slow addition of LiTMP to a solution of the epoxide substrate at 0 °C, followed by warming to ambient temperature. This method provides the anti-product isomer, a stereochemical outcome that is complementary to that observed in the Simmons–Smith cyclopropanation reaction, which otherwise leads to cis-isomer 28 as a consequence of known directing effects in the reaction of allylic alcohols. 1.4 Cycloisomerization In 1976, Ohloff and co-workers reported a seminal observation in which propargylic acetate 29 was 25 converted to 30 in 70% yield upon exposure to ZnCl2 (Scheme 6). Intriguingly, cyclopropane 31 was formed as a side product in minor amounts (5%). Some years later, Rautenstrauch described a novel approach for the synthesis of cyclopentenones, a transformation which is referred to as the Rautenstrauch rearrangement.26 When enyne 32 was exposed to a Pd(II) catalyst, cyclopentenone 33 was isolated in 50-61% yield. Rautenstrauch proposed a mechanism in which the alkyne undergoes acetoxy palladation to give intermediate 34. Subsequent displacement of the acetoxonium by the vinyl-palladium species furnishes a putative palladacycle (35) that is suggested to undergo reductive elimination and hydrolyze to form 33. D Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses Scheme 6. Cycloisomerization of propargylic acetates by Ohloff and Rautenstrauch. A pivotal discovery was made by Fensterbank and Malacria when dienyne 36 was exposed to PtCl2 at elevated temperatures (Scheme 7).27 The free alcohol substrate as well as the corresponding methyl and silyl ethers provided 38, while the acetate derivatives gave 37. The authors suggested that in the absence of an acetate, zwitterion 41 cyclizes to cyclopropane 42. The generated intermediate platinum carbene then participates in a second intramolecular cyclopropanation reaction to yield 38. For the acetylated substrate, an acetoxonium organoplatinum intermediate is formed (39) analogous to 34 which leads to metallocarbene that subsequently is engaged in an intramolecular cyclopropanation to afford 37. Building on these discoveries, Toste reported a remerkable gold(I)-catalyzed Rautenstrauch rearrangement, generating cyclopentenones from propargylic pivalates in high yields.28 Additionally, Fürstner and co-workers reported a versatile gold- and platinum-catalyzed method for the synthesis of cyclopropane substituted cyclopentanones from propargylic acetates.29 E Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses Scheme 7. Pt-catalyzed cycloisomerization of enynes and the effect of oxygen substitution. A conceptually different cycloisomerization was reported by Trauner and Miller in 2003, inspired by biosynthetic considerations (Scheme 8).30 The focus of the studies by Trauner was the synthesis of polyketides featuring a bicyclo[3.1.0]hexane core, such as photodeoxytridachione (43), tridachiapyrone (44) and crispatene (45). In order to establish efficient entry into this natural product class, a novel Lewis